The scorpion toxin Tf2 is a relatively large toxin and the first identified β-scorpion toxin extracted from the venom of the Brazilian scorpion Tityus fasciolatus. It is a neurotoxin that shifts the activation of voltage-gated sodium NaV1.3 channel isoforms to more negative values allowing opening near the resting membrane potential. Tf2 specificity is not strictly limited to NaV1.3 channels, it also acts on NaV1.9 sodium channels.
Etymology and Source Tf2 gets its name from the Brazilian scorpion Tityus fasciolatus which is the origin species. The Tityus fasciolatus is a scorpion found in Brazil in the Cerrado biome; it is phylogenetically related to Tityus serrulatus. Tf2 toxin comes from the venom of the endemic species Tityus fasciolatus, which is a scorpion from the family of Buthidae.
Chemistry
Structure
The nucleotide sequence that codes for Tf2 consists of 255 nucleotides. Tf2 is a relatively large toxin, which is stabilized by disulfide crosslinks. It is composed of 64 amino acid residues: MKRFLLFISILMMIGTIVVGKEGYAMDHEGCKFSCFIRPSGFCDGYCKTHLKASSGYCAWPACYCYGVPSNIKVWDYATNKCGK. The structural characteristics of the β-scorpion toxins allow it to affect sodium channels. Like some other toxins originating from the Tityus genus, Tf2 contains a cluster of aromatic residues formed by Y4, Y37, Y44, Y46, W40 and W55, and these determine its function on the nervous system. Tf2 possesses a positive electrostatic potential at position 1 (K1), a negative electrostatic potential at position 2 (E2), and a positively charged group at position 12 (K12).. The positive charges at position 1 and 12 and the negative charge at position 2 determine the function of the toxin on voltage gated sodium channels. In a three-dimensional model, the negative residue is central and surrounded by an aromatic core creating a specific binding interface.
Homology and Family The Tf2 sequence and respective positions of electrostatic charges are very typical for the Tityus genus of scorpion toxins. As a toxin, Tf2 is identical to the toxin Tb2-II which is found in Tityus bahiensis. Tf2 is similar in sequence to several other toxins from the genus; the sequence homology classifies it as a β-scorpion toxin.
Target Tf2 is a mammal-selective peptide toxin that modulates voltage-gated sodium channels (NaV). As it primarily targets the mammalian NaV1.3 and NaV1.9 isoforms and has no measurable effect on seven other NaV isoforms (NaV1.1-1.2; NaV1.4-1.8).
Mode of Action As a β-scorpion toxin, Tf2 interacts with the voltage sensors of NaV channels. During its action, Tf2 induces a hyperpolarizing shift in the voltage-dependence of activation, changing the half-activation voltage (V50) to more negative values. For the NaV1.3 subtype, 1μM of Tf2 shifts the V50 from control values of approximately –29.5 mV to –33.1 mV down to –40.8 mV to –49.3 mV. A similar effect is observed on the NaV1.9 subtype, where V50 is shifted from approximately –55.1 mV to -61.4 mV. As a result, the channels open at membrane potentials closer to the resting membrane potential, which causes early channel opening. Tf2 also causes a significant decrease in the peak current and an increase in slope factor for the NaV1.3 activation curve (from approximately 3.5 mV to about 8.0-8.9 mV). This indicates that Tf2 reduces the channel's maximum open probability, meaning that even at highly depolarized potentials, the toxin-bound channels do not open as effectively as unbound channels, thus reducing the total peak sodium current.
Toxicity Tf2-specific toxic effects remain unknown in humans, but was presented in mouse model: Mice injected with 1μM of Tf2 display spontaneous pain behaviour (e.g., licking, flinching), erythema and swelling. These responses to a Tf2 injection are present even when NaV1.3 and NaV1.9 activity have been inhibited.
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